Cystic fibrosis (CF) is an autosomal recessive genetic disease, characterized by pulmonary and sinus disease, and gastrointestinal and reproductive tract dysfunction. The disease is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which encodes for an apical membrane epithelial protein that functions as a c-AMP-regulated chloride channel and a regulator of other channels. Defective CFTR results in abnormal ion transport and depleted airway surface liquid volume with reduced mucociliary clearance and a propensity for chronic infection of the respiratory tract with resulting inflammation, progressive airway damage and bronchiectasis. CF patients suffer from chronic repeated cycles of pulmonary bacterial colonization, pulmonary exacerbations and chronic lung function decline, which often lead to premature death. Although improved treatment of lung disease has increased survival, the median predicted age for survival is only 35 years, and patients continue to have significant morbidity, including hospitalizations.
Nucleotide P2Y2 agonsists, such as uridine 5-triphosphate (UTP) and diquafosol tetrasodium [P1, P4-di(uridine 5′-) tetraphosphate, tetrasodium salt], regulate certain activities of the human airway epithelium. The P2Y2 receptor is abundant on the luminal surface of polarized epithelial cells, especially those lining muscosal surfaces exposed to the external environment. P2Y2 agonsists act by stimulating the P2Y2 receptor, which results in the secretion of chloride ion (Cl−) and liquid and the inhibition of sodium (Na+) absorption to hydrate the airway surface liquid layer and to create a more normal periciliary fluid milieu. P2Y2 agonists also act by stimulating mucin secretion from goblet cells and increasing ciliary beat frequency.
P2Y2 receptor agonists represent a new approach to the treatment of CF, which bypasses the defective CFTR chloride channel, and activates an alternative chloride channel. This activation results in an increase in airway surface epithelial hydration, and through these actions and effects on cilia beat frequency, increases mucociliary clearance. Denufosol tetrasodium [P1-(uridine 5′-)-P4-(2′-deoxycytidine 5′-) tetraphosphate, tetrasodium salt], a chemically stable, selective P2Y2 receptor agonist, has been investigated in clinical trial studies as a treatment for patients with CF. (Kellerman, et al., Pulm Pharmacol Ther., 21: 600-7, 2008; Deterding, et al., Pediatric Pulm 39: 339-348, 2005; Yerxa, et al., J. Pharmacol Exo Ther., 302: 871-880, 2002.)
Macrolides are a group of broad spectrum antibiotics. Macrolides include natural macrolides that are produced by various strains of Streptomyces (spore forming bacteria that grow slowly in soil or water as a branching filamentous mycelium similar to that of fungi) and man-made macrolides that are similar in structure to the natural macrolides; both groups have a complex chemical (macrocyclic) structure. They act by inhibiting protein synthesis, specifically by blocking the 50S ribosomal subunit.
ZITHROMAX® (azithromycin tablets and azithromycin for oral suspension) is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of microorganisms producing sexually transmitted diseases such non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis. Azithromycin alone or in combination with other drugs is used for the profilaxis and treatment of mycobacterial infections such as disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infection.
Macrolides such as azithromycin when taken orally by patients can have adverse effects related to gastrointestinal, cardiovascular (prolongation of QT interval), genitourinary, nervous system (dizziness and headache), and allergic reaction. Most of the side effects leading to discontinuation of ZITHROMAX® in clinical trials were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain (ZITHROMAX® Product Insert). Adverse effects of oral azithromycin could potentially interfere with the often impaired delicate gastrointestinal system of patients; thus it could interfere with absorption of nutrient or other concomitant medications that those patients must take every day, including dietary supplements.
There is a need for an improved method for treating cystic fibrosis; such method is not only effective to treat cystic fibrosis but also does not have significant adverse effects.